Project Summary: My laboratory is interested in understanding molecular basis and functions for two signaling pathways that use seven transmembrane receptors in their signaling transduction. One of the pathways is mediated by G protein-coupled receptors, and the other is activated by Wnt proteins. We have been using a combination of biochemical, molecular and cell biological, transgenic, genomic, proteomic, structural and chemical biological approaches to discover novel signaling mechanisms and investigate their functions in vitro and in vivo. In this R35 application, I intend to streamline our current four research projects that are pertinent to NHBLI missions under one funding mechanism. Two of the projects are current funded by NHBLI. These four projects are: 1) To test the hypothesis that the initial break of the symmetry may arise from PM PI4P polarization caused by plasma membrane deformation as the result of cell attachment. Polarized PM PI4P defines the ?uropod? and thus the initial cellular polarity, upon which further polarization stimulated by chemoattractants is extended. 2) To investigate the sustained signaling pathway for regulation of fibroblast migration and its therapeutic potential in treating pulmonary fibrosis. 3) To Investigate the hypothesis that increased exocytosis is a pathogenic basis for CCM disease. 4) To investigate MEKK3 as being a negative regulator of NADPH oxidase 2 (NOD2) and potential therapeutic target for acute respiratory distress syndrome. Each of the project is highly innovative and would exert a strong impact in their respective field. In addition, we are generating the new leads coming from these high risk/high reward studies that include functional genomic screens based on the CRISPR/Cas9 and RNAi technologies. Thus, this R35 mechanism would not only allow streamlining our grant application and management so that we can better focus our effort on research, but also afford us the flexibility to fully and efficiently pursue the new leads coming from these high risk/high reward studies. Our track record strongly indicates our readiness, capability, and success to pursue subjects that we deem to be of high-impact even though they fall outside our initial intents.